PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration
Abstract Background Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard,...
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doaj-5a3b6ad8577f451985f8de077a5150d52021-01-10T12:13:31ZengBMCStem Cell Research & Therapy1757-65122021-01-0112111110.1186/s13287-020-02086-8PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regenerationNing Zhang0Chi-Wen Lo1Takeshi Utsunomiya2Masahiro Maruyama3Ejun Huang4Claire Rhee5Qi Gao6Zhenyu Yao7Stuart B. Goodman8Department of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityDepartment of Orthopaedic Surgery, Stanford UniversityAbstract Background Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. Methods In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis. Results PDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. Conclusions Overexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.https://doi.org/10.1186/s13287-020-02086-8Interleukin-4Platelet-derived growth factorCo-overexpressionGenetically modified mesenchymal stem cellsBone regeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ning Zhang Chi-Wen Lo Takeshi Utsunomiya Masahiro Maruyama Ejun Huang Claire Rhee Qi Gao Zhenyu Yao Stuart B. Goodman |
spellingShingle |
Ning Zhang Chi-Wen Lo Takeshi Utsunomiya Masahiro Maruyama Ejun Huang Claire Rhee Qi Gao Zhenyu Yao Stuart B. Goodman PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration Stem Cell Research & Therapy Interleukin-4 Platelet-derived growth factor Co-overexpression Genetically modified mesenchymal stem cells Bone regeneration |
author_facet |
Ning Zhang Chi-Wen Lo Takeshi Utsunomiya Masahiro Maruyama Ejun Huang Claire Rhee Qi Gao Zhenyu Yao Stuart B. Goodman |
author_sort |
Ning Zhang |
title |
PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration |
title_short |
PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration |
title_full |
PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration |
title_fullStr |
PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration |
title_full_unstemmed |
PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration |
title_sort |
pdgf-bb and il-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration |
publisher |
BMC |
series |
Stem Cell Research & Therapy |
issn |
1757-6512 |
publishDate |
2021-01-01 |
description |
Abstract Background Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect. Methods In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis. Results PDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone. Conclusions Overexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation. |
topic |
Interleukin-4 Platelet-derived growth factor Co-overexpression Genetically modified mesenchymal stem cells Bone regeneration |
url |
https://doi.org/10.1186/s13287-020-02086-8 |
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